Macrolides are a group of chemical compounds, some of which have antibacterial activity and are useful in the therapy of bacterial infections in mammals. Macrolide antibiotics include those having a many-membered lactone ring to which are attached one or more deoxy sugar molecules. These antibiotics are generally bacteriostatic, but have been also been shown to be bacteriocidal to some organisms. Macrolide antibiotics are effective against gram-positive cocci and bacilli, although some of them do possess some activity against some gram-negative organisms. Macrolide antibiotics exert their bacteriostatic activity by inhibiting bacterial protein synthesis. (“Goodman & Gillman's the Pharmacological Basis of Therapeutics,” 9th ed., J. G. Hadman & L. E. Limbird, eds., ch. 47, pp. 1135-1140, McGraw-Hill, New York (1996)).
As a class macrolides tend to be colorless and usually crystalline. The compounds are generally stable in near neutral solution, but may be less stable in acid or base solutions. The precursors of macrolide compounds used in the process of the invention (e.g. (9E)-9-deoxy-9-hydroxyiminoerythromycin A (hereinafter “Structure 1”); 9-(Z)-erythromycin oxime (hereinafter “Structure 2”); and 9-Deoxo-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a homoerythromycin A (hereinafter “Structure 3”) have been described in U.S. Pat. Nos. 5,202,434 and 5,985,844. Furthermore, Yang et al., Tetrahedron Letters, 1994, 35(19), 3025-3028 and Djokic et al., J. Chem. Soc. Perkin Trans. 1, 1986, 1881-1890 describe the synthesis of macrolide compounds that use these compounds as intermediates. However, the synthesis and isolation of macrolide compounds such as gamithromycin typically requires multiple extractions and phase separations.
Therefore, there is still a need for simplifying the synthesis and isolation of macrolides as well as increasing the stability of the macrolides and intermediates thereof.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.